Transcription factor Dmrt1 triggers the SPRY1-NF-κB pathway to maintain testicular immune homeostasis and male fertility

Abstract

Bacterial or viral infections, such as Brucella, mumps virus, herpes simplex virus, and Zika virus, destroy immune homeostasis of the testes, leading to spermatogenesis disorder and infertility. Of note, recent research shows that SARS-CoV-2 can infect male gonads and destroy Sertoli and Leydig cells, leading to male reproductive dysfunction. Due to the many side effects associated with antibiotic therapy, finding alternative treatments for inflammatory injury remains critical. Here, we found that Dmrt1 plays an important role in regulating testicular immune homeostasis. Knockdown of Dmrt1 in male mice inhibited spermatogenesis with a broad inflammatory response in seminiferous tubules and led to the loss of spermatogenic epithelial cells. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed that Dmrt1 positively regulated the expression of Spry1, an inhibitory protein of the receptor tyrosine kinase (RTK) signaling pathway. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) analysis indicated that SPRY1 binds to nuclear factor kappa B1 (NF-κB1) to prevent nuclear translocation of p65, inhibit activation of NF-κB signaling, prevent excessive inflammatory reaction in the testis, and protect the integrity of the blood-testis barrier. In view of this newly identified Dmrt1- Spry1-NF-κB axis mechanism in the regulation of testicular immune homeostasis, our study opens new avenues for the prevention and treatment of male reproductive diseases in humans and livestock.

Keywords: Dmrt1; NF-κB; Orchitis; Spermatogenesis; Spry1.

Figure 1

Targeted disruption of Dmrt1 causes infertility and abnormal spermatogenesis in mice

Figure 2

Identification of Dmrt1 as a key regulator for inflammatory responses

Figure 3

Identification of DMRT1-occupancy sites

Figure 4

Dmrt1 directly regulates positive expression of Spry1

Figure 5

Spry1 regulates BTB and testicular immune homeostasis

Figure 6

Spry1 inhibits NF-κB signaling pathway to decrease immune response in SCs

Figure 7

SPRY1 prevents NF-κB nuclear translocation by binding to ANK domain

Figure 8

Role of DMRT1 and SPRY1 in SCs